DESCRIPTION: This re-submitted proposal seeks continued funding for the Pancreatic Cancer Genetic Epidemiology (PACGENE) Consortium, a multicenter, multidisciplinary team which has the goal to identify susceptibility genes for familial pancreatic cancer (FPC). The PACGENE Consortium has shown that coordinated case finding, family recruitment, and linkage analysis are productive: we have identified three novel regions, and are positioned to use the pedigree material to further gene discovery. The PACGENE Consortium comprises 7 data collection/analysis centers in the U.S. and Canada, 2 Cores (Data Management/Analysis and Pathology/Tissue Genotyping), and is guided by Steering and External Advisory Committees. Our specific aims are: AIM 1. To validate linkage findings for gene discovery with an extended, final sample of FPC families. We will: a) Develop a set of 63 new FPC pedigrees and follow up our existing cohort of FPC pedigrees to increase their informativeness; b) Perform a genomewide (~6008 single nucleotide polymorphism (SNP)) validation linkage analysis (genotyping will be sought at the Center for Inherited Disease Research (CIDR) at no cost to this grant); AIM 2. To perform a familial case-control association study to validate SNP associations identified in other consortia studies. We will genotype 800 FPC probands and 800 unrelated family controls using a custom SNP marker panel identified by the PanScan genomewide association study of the Cohort Consortium, the Pancreatic Cancer Case-Control Consortium, and our own linkage analyses; AIM 3. To identify the genes in candidate regions identified by linkage and association. We will: a) Fine map regions identified through linkage analyses (including chromosomes 2p, 2q, and 10q); b) Perform genomewide loss of heterozygosity allelotyping of microdissected early stage tumors (PanINs and IPMNs) from FPC probands (comparing tumor to normal), with a focus on regions of interest; c) Resequence the best candidate genes in the regions identified. Public Health Relevance: Over 37,000 new cases of pancreatic cancer will occur in the U.S. in 2007, almost all rapidly fatal. Our research will help identify the genes for FPC, furthering knowledge about the etiology of pancreatic cancer that should accelerate translation to care. Risk assessment will be improved, and identified FPC genes will lead to development of more effective strategies for early detection, prevention, and therapy. PUBLIC HEALTH RELEVANCE: Over 37,000 new cases of pancreatic cancer will occur in the U.S. in 2007, almost all rapidly fatal. Our research will help identify the genes for familial pancreatic cancer (FPC), furthering knowledge about the cause(s) of pancreatic cancer that should accelerate translation to care. Risk assessment will be improved, and identified FPC genes will lead to development of more effective strategies for early detection, prevention, and therapy.